The Mutational Spectrum of Pre- and Post-Neoadjuvant Chemotherapy Triple-Negative Breast Cancers.

The response of triple-negative breast cancer (TNBC) patients to pre-operative (neoadjuvant chemotherapy) is a critical factor of their outcome. To determine the effects of chemotherapy on the tumor genome and to identify mutations associated with chemoresistance and sensitivity, we performed whole exome sequencing on pre/post-chemotherapy tumors and matched lymphocytes from 26 patients. We observed great inter-tumoral heterogeneity with no gene mutated recurrently in more than four tumors besides TP53. Although the degree of response to chemotherapy in residual tumors was associated with more subclonal changes during chemotherapy, there was minimal evolution between pre/post-tumors. Indeed, gene sets enriched for mutations in pre- and post-chemotherapy tumors were very similar and reflected genes involved in the biological process of neurogenesis. Somatically mutated genes present in chemosensitive tumors included COL1A2, PRMD15, APOBEC3B, PALB2 and histone protein encoding genes, while BRCA1, ATR, ARID1A, XRCC3 and genes encoding for tubulin-associated proteins were present in the chemoresistant tumors. We also found that the mutational spectrum of post-chemotherapy tumors was more reflective of matching metastatic tumor biopsies than pre-chemotherapy samples. These findings support a portrait of modest ongoing genomic instability with respect to single-nucleotide variants induced by or selected for by chemotherapy in TNBCs.

Prognostic and predictive value of circulating tumor DNA during neoadjuvant chemotherapy for triple negative breast cancer.

Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) is highly prognostic and determines whether adjuvant chemotherapy is needed if residual tumor is found at surgery. To evaluate the predictive and prognostic values of circulating tumor DNA (ctDNA) in this setting, we analyzed tumor and serial bloods from 26 TNBC patients collected prior, during, and after NAC. Individual digital droplet PCR assays were developed for 121 variants (average 5/patient) identified from tumor sequencing, enabling ctDNA detection in 96% of patients at baseline. Mutant allele frequency at baseline was associated with clinical characteristics. Levels drastically fell after one cycle of NAC, especially in patients whose tumors would go on to have a pathological complete response (pCR), but then rose significantly before surgery in patients with significant residual tumor at surgery (p = 0.0001). The detection of ctDNA early during treatment and also late at the end of NAC before surgery was strongly predictive of residual tumor at surgery, but its absence was less predictive of pCR, especially when only TP53 variants are considered. ctDNA detection at the end of neoadjuvant chemotherapy indicated significantly worse relapse-free survival (HR = 0.29 (95% CI 0.08-0.98), p = 0.046), and overall survival (HR = 0.27 95% CI 0.075-0.96), p = 0.043). Hence, individualized multi-variant ctDNA testing during and after NAC prior to surgery has prognostic and predictive value in early TNBC patients.

Imaging of Thoracic Wall Abnormalities.

Identification of certain abnormalities of the chest wall can be extremely helpful in correctly diagnosing a number of syndromic conditions and systemic diseases. Additionally, chest wall abnormalities may sometimes constitute diagnoses by themselves. In the present pictorial essay, we review a number of such conditions and provide illustrative cases that were retrospectively identified from our clinical imaging database. These include pentalogy of Cantrell, Klippel-Feil syndrome, cleidocranial dysplasia, Poland syndrome, osteopetrosis, neurofibromatosis type 1, Marfan syndrome, Gardner syndrome, systemic sclerosis, relapsing polychondritis, polymyositis/dermatomyositis, ankylosing spondylitis, hyperparathyroidism, rickets, sickle cell anemia, thalassemia, tuberculosis, septic arthritis of the sternoclavicular joint, elastofibroma dorsi, and sternal dehiscence.

Thoracic Diseases With Musculoskeletal Manifestations and Vice Versa: A Review.

OBJECTIVE: The purpose of this article is to review several thoracic conditions that are associated with certain musculoskeletal radiological abnormalities using imaging of patients with concomitant chest and musculoskeletal manifestations as illustrative examples. CONCLUSION: Radiologic findings of many thoracic diseases are often nonspecific. When standing alone, their interpretation commonly results in long differential diagnosis. However, in certain instances, a reasonably accurate diagnosis can be made based on imaging findings alone.

The identification of challenges in tissue collection for biomarker studies: the Q-CROC-03 neoadjuvant breast cancer translational trial experience.

One of the major challenges in biomarker development is the collection of tumor tissue of adequate quality for analysis. A prospective clinical trial was initiated to collect tissues from triple negative breast cancers prior to and after neoadjuvant chemotherapy in order to study the mechanisms of chemoresistance. Sixty patients had pre-chemotherapy biopsies performed by either a surgeon or a radiologist, while those with residual tumor after chemotherapy had research-only biopsies and/or surgical samples collected in liquid nitrogen, RNA-later and formalin. We examined each core for tumor cellularity, stromal content, and necrosis after which, RNA and DNA extraction was performed. We found that biopsies collected with ultrasound guidance were more likely to contain tumor than those collected by the surgeon. Patient reluctance to undergo research-only biopsies after chemotherapy was not a problem. Pre-chemotherapy tumor biopsies frequently did not contain any tumor cells (15%) or did not have ≥50% tumor content (63%). Indeed, 50% of patients had at least 2 pre-chemotherapy core biopsies with <50% tumor content. After chemotherapy, 30% of biopsy or surgical samples in patients with incomplete response did not contain any tumor. Finally, RNA-later not only made histopathological assessment of tumor content difficult, but yielded less DNA than fresh snap frozen samples. We recommend that high-quality tissue procurement can be best accomplished if at least three image-guided core biopsies be obtained per sample, each of these cores be examined for tumor cellularity and that at least some of them be freshly snap frozen in liquid nitrogen.

Posterior Hoffa's fat pad impingement secondary to a thickened infrapatellar plica: a case report and review of the literature.

We report a case of posterior hoffitis in a middle-aged woman with no prior history of significant major trauma. Her symptoms of anterior knee pain and limited extension failed conservative measures. Preoperative magnetic resonance imaging demonstrated a significantly thickened infrapatellar plica tethering Hoffa's fat pad in the anterior interval of the knee. Arthroscopic resection of the infrapatellar plica resulted in complete resolution of symptoms within six months following the surgery.

Review of Thoracic Imaging Findings Unique to Women.

PURPOSE: Traditionally, indications for imaging studies of women are considered to be related to screening for and evaluation of disease of the female breast and pelvis. However, a number of chest diseases and associated intrathoracic imaging findings are unique to women and should be recognized by general radiologists, as well as chest and women-imaging specialists. CONCLUSIONS: The sex-specific findings unique to women include normal anatomical variants, primary lung disease, complications of breast and gynaecological disease, and pregnancy-related conditions. Classification, description, and illustration of gender-specific chest imaging findings are the objective of this article.

Imaging characteristics of spindle cell lipoma and its variants.

A spindle cell lipoma (SCL) is a relatively common tumor that can be challenging to the radiologist, pathologist, or surgeon to diagnose, particularly when internal fat content is scant or absent. Although these lesions may be found at various locations, the typical presentation for this lesion is a well-circumscribed and non-aggressive subcutaneous mass in the posterior neck presenting in a middle-aged to elderly man. In this article, the typical and atypical imaging characteristics of a spindle cell lipoma (SCL) will be reviewed. Knowledge of the common imaging and pathologic features of SCLs can help suggest the diagnosis and guide patient management.

Nonthrombotic pulmonary embolism.

OBJECTIVE: The purpose of this essay is to highlight the clinical features and imaging findings associated with different types of nonthrombotic pulmonary embolism. CONCLUSION: Nonthrombotic pulmonary embolism is an infrequent condition with various causes that can be life-threatening pathologic conditions. The entity presents a diagnostic challenge because of the low specificity of clinical symptoms and imaging signs. Awareness of the imaging features of nonthrombotic pulmonary embolism facilitates correct diagnosis and leads to appropriate patient care.

Valid MR imaging predictors of prior knee arthroscopy.

PURPOSE: To determine whether fibrosis of the medial patellar reticulum (MPR), lateral patellar reticulum (LPR), deep medial aspect of Hoffa's fat pad (MDH), or deep lateral aspect of Hoffa's fat pad (LDH) is a valid predictor of prior knee arthroscopy. MATERIALS AND METHODS: Institutional review board approval and waiver of informed consent were obtained for this HIPPA-compliant study. Initially, fibrosis of the MPR, LPR, MDH, or LDH in MR imaging studies of 50 patients with prior knee arthroscopy and 100 patients without was recorded. Subsequently, two additional radiologists, blinded to clinical data, retrospectively and independently recorded the presence of fibrosis of the MPR in 50 patients with prior knee arthroscopy and 50 without. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for detecting the presence of fibrosis in the MPR were calculated. κ statistics were used to analyze inter-observer agreement. RESULTS: Fibrosis of each of the regions examined during the first portion of the study showed a significant association with prior knee arthroscopy (p < 0.005 for each). A patient with fibrosis of the MPR, LDH, or LPR was 45.5, 9, or 3.7 times more likely, respectively, to have had a prior knee arthroscopy. Logistic regression analysis indicated that fibrosis of the MPR supplanted the diagnostic utility of identifying fibrosis of the LPR, LDH, or MDH, or combinations of these (p ≥ 0.09 for all combinations). In the second portion of the study, fibrosis of the MPR demonstrated a mean sensitivity of 82%, specificity of 72%, PPV of 75%, NPV of 81%, and accuracy of 77% for predicting prior knee arthroscopy. CONCLUSIONS: Analysis of MR images can be used to determine if a patient has had prior knee arthroscopy by identifying fibrosis of the MPR, LPR, MDH, or LDH. Fibrosis of the MPR was the strongest predictor of prior knee arthroscopy.

Analysis of arterial blood vessels surrounding the myoma: relevance to myomectomy.

OBJECTIVE: The optimal direction of myomectomy incision in relation to the blood vessels is unclear. Accordingly, we evaluated the location and course of arterial blood vessels surrounding the myoma. METHODS: This study is a retrospective analysis of 592 arterial blood vessels in 60 patients with symptomatic uterine leiomyomata undergoing uterine artery embolization. RESULTS: We encountered 592 arterial blood vessels surrounding the myoma. The vessels could be seen encircling the surface of the myoma. The dominant myoma was located on anterior (n=30), posterior (n=17), and fundal part of the uterus (n=13). There was no difference in the diameter (6.9+/-2.7 cm, 5.8+/-0.7 cm, and 6.7+/-0.5 cm) and volume of the myoma (268.6+/-52.7 cm(3), 197.0+/-64.5 cm(3), and 199.3+/-40.5 cm(3)) among anterior, posterior, and fundal, respectively. The vessels were graded as coursing with angles of 0-30 degrees, 30-60 degrees, and 60-90 degrees. There were significantly more blood vessels in the 30-60 degree group among anterior myoma (n=88, 42.5%) than in 0-30 degree (n=59, 28.5%, P=.004, 95% confidence interval [CI] 0.36-0.81) and 60-90 degree groups (n=60, 29.0%, 95% CI 1.2-2.7). Similar findings were found among posterior myoma (0-30 degrees n=26, 21.7%; 30-60 degrees n=59, 49.2%; P<.001, 95% CI 0.16-0.50; 60-90 degrees 35 (29.2%), P<.002, 95% CI 1.37-3.9). Among fundal myomas, there was no difference in the number of vessels in the 0-30 degree (n=28, 28.6%), 60-90 degree (n=40, 40.8%), and in 60-90 degree groups (n=30, 30.6%). CONCLUSION: Arterial blood vessels travel mostly diagonally on the surface of anterior and posterior myomas. There was no predominant pattern in the course of the arteries on fundal myomas. These findings suggest that regardless of the direction of the myomectomy incision, arterial blood vessels on myoma surface could be injured. LEVEL OF EVIDENCE: II.

Il Fasciculo di Medicina of 1493: medical culture through the eyes of the artist.

THE FASCICULUS MEDICINA, printed in 1491, is considered the first illustrated medical book. The Latin essays and illustrations in this volume provide insight into the medical knowledge of Western Europe and, in the Italian edition published in 1493, glimpses into the medical culture of the late 15th century. We outline the scientific and social environments into which the Fasciculus Medicinae of 1491 was introduced and the transition that occurred with the publication of the 1493 Italian edition. The artist of the 1493 Fasciculo witnessed a paradigm shift occurring. In four woodcuts, the artist captured four themes: the relevance of knowledge-based medicine, the emergence of laboratory medicine, the Hippocratic lessons of patient observation, and the emerging revolution in anatomy.

Quality of fertility clinic websites.

OBJECTIVE: To evaluate the overall quality of the Society for Assisted Reproductive Technology (SART)-affiliated fertility clinic websites, according to American Medical Association (AMA) Internet health information guidelines. DESIGN: Cross-sectional evaluation. SETTING: Two hundred sixty-six websites drawn from the SART directory and the World Wide Web. INTERVENTION(S): Three objective scoring scales (ownership, content, and navigation) adapted from AMA guidelines. MAIN OUTCOME MEASURES: Seven objective criteria for ownership, 8 for content, and 11 for website navigation. RESULT(S): Two thirds of SART-affiliated fertility clinics have functional websites. Of the 236 sites evaluated, 58 belong to hospital centers. Overall, the scores for the three scoring scales were low. Compared with the websites of non-hospital clinics, those of hospital centers were more likely to include information about site ownership and affiliations (89.7% vs. 60.7%) and patient privacy (34.5% vs. 20.8%). Also, contents of hospital center websites were significantly easier to distinguish from advertisements (70.7% vs. 47.7%), and reference sources for specific contents were easier to identify (27.6% vs. 8.4%). Hospital center websites were more likely to indicate affiliations and financial disclosures of authors (25.9% vs. 10.7%), to feature a site map (25.9% vs. 12.3%), and to have a search function (31.0% vs. 5.6%). CONCLUSION(S): Websites of SART-affiliated clinics fail to meet most of the AMA health information guidelines. The quality of the hospital centers' websites is better than that of private clinics.

A call for standardization of fertility clinic websites.

Websites for Society for Assisted Reproductive Technology-affiliated clinics fail to meet most American Medical Association health information guidelines. Professional organizations in reproductive medicine need to standardize the accuracy and appropriateness of online reproductive health information.